In the present specification, the term "water swelling polymer gel" means a polymer gel, being capable of swelling in body fluids such as blood, plasma and intercellular fluid or fluids similar to body fluids, and having biocompatibility. As such water swelling polymer gel consisting of polysaccharide, it is known a gel composed of agar, agarose and carrageenan. Chemically crosslinked dextran or cellulose gel, calcium-ion crosslinked alginate gel, and a gel composed of chitin or chitosan are also known.
The application of water swelling polymer gels to medical practice is exemplarily found in wound dressings, contact lens, intraocular lens, adhesives for biological tissues, adhesion preventing materials, adsorbents for blood purification, hybrid artificial organs such as artificial pancreas and artificial liver, artificial cartilage, base materials for releasing drugs in a sustained manner and the like. Because water swelling polymer gels have compositions and mechanical properties similar to those of biological tissues, such gels may be applied in a wide variety of fields in the future.
Gauze and ointments have been used conventionally for treating wounds such as injury and burn, ulcer, and decubitus. These have effects of absorbing exudates and preventing the penetration of exogenous bacteria and the like. It has been indicated recently that a variety of growth factors (bFGF, TGF.beta., etc.) promoting wound healing are present in the exudates from the wounds (see Howell, J. M., Current and Future Trends in Wound Healing, Emerg. Med. Clin. North Amer., 10, 655-663 (1992)). Therefore, attention has been focused on an occlusive dressing having the effect of promoting wound healing while holding the growth factor on the wound (Eaglstein, W. E., Experience with biosynthetic dressings, J. Am. Acad. Dermatol., 12, 434-440 (1985)).
As the occlusive dressings, use may be made of polyurethane film, hydrocolloid, non-woven fabric of alginate fiber, polyvinyl alcohol sponge, and water swelling polymer gels comprising polyethylene glycol and polyacrylamide.
As such adhesive for biological tissues, use may be made of cyanoacrylate polymerizable adhesives, fibrin glue and the like.
As adhesion preventing agents, those composed of oxycellulose mesh are known.
As the method for producing these water swelling polymer gels, it is known a method of producing solid matters of amylose, dextran or pullulan, crosslinked with succinate or glutarate (see the Specification of U.S. Pat. No. 4,002,173). These are preferable as a hemostatic agent. Also, it is known crosslinked chitosan produced by reacting chitosan with N-hydroxysuccinimide ester (see Japanese Patent Laid-open No. Hei 2-180903). This is useful in the field relating to medicines, such as artificial skins. Furthermore, viscous and elastic fluid is also produced by ionically crosslinking temporarily a chitin derivative with sulfuric acid, aspartic acid, glutamic acid and the like, and is used for preventing adhesion (see the Specification of U.S. Pat. No. 5,093,319).
As the essential property, however, biocompatibility should be demanded for the medical material in addition to the usefulness for medical purpose. A great number of medical materials have been developed conventionally, but it has not yet been known any material with biocompatibility, which can satisfy all of various medical use. Attempts have been made of the application of water swelling polymer gels consisting of polysaccharide having the composition and mechanical properties similar to those of living bodies to medical purpose, but because the stability and strength of the gels are low, few of them can be resistant to steam sterilization. Thus, the gels are problematic as medical devices.
Sterilization essential for the production of medical devices includes formalin sterilization, ethylene oxide gas sterilization, steam sterilization, or radiation sterilization. In the formalin sterilization and ethylene oxide gas sterilization of water swelling polymer gels, complete removal of residual drugs is hard, involving possible residual toxicity. Steam sterilization is a highly safe sterilization process with no residual matters, and the apparatus therefor is not expensive. However, few water swelling polymer gels can resist the severe sterilization conditions of 121.degree. C. for 20 minutes. Radiation sterilization is a highly safe sterilization method with no residual matters, but the method is problematic because the irradiation systems are expensive and the properties of water swelling polymer gels may be modified due to radiation generated radicals from water, which may cleave chemical bonds and induce crosslinking reactions.
Additionally, gels of agar, agarose, carrageenan and the like are not suitable as the structural component of medical devices because the gels with a lower mechanical strength dissolve under heating. Gels of crosslinked dextran or cellulose do not dissolve under heating, but the gels may turn rigid by a crosslinking process and acquires a low water content, involving poor biocompatibility. Furthermore, the gels may be colored or may be opaque through crosslinking. Calcium ion-crosslinked alginate gel with a higher crosslinking degree may be semi-opaque or the gel may gradually dissolve in body fluid or in physiological salt solutions during ion exchange, problematically. Also, the gel has a lower mechanical strength so that the gel is readily broken. It is also problematic that chitin and chitosan dissolve in body fluid or they may be solubilized via bacterial infection.
Polyurethane film to be used as wound dressings is not water absorbable although the film has higher transparency and occlusive potential, so the film cannot be used for the wounds with much exudates. Non-woven fabric composed of alginate fiber hydrocolloid, polyvinyl alcohol sponge and the like, all have retentivity of exudates. Because they are opaque, however, wounds cannot be observed. Furthermore, hydrocolloid dressings do not have bioabsorbability, and therefore, the principal components thereof remain in biological tissues for a long term, inducing chronic inflammation, disadvantageously (see Young, S. R. et. al., J. Invest. Comparison of the effect of semi-occlusive polyurethane dressings and hydrocolloid dressings on dermal repair: 1. Cellular changes. Dermatol., 97, 586-592 (1991)). Some of the water swelling polymer gels composed of polyethylene glycol and polyacrylamide have good transparency, but without bioabsorbability because the gels are synthetic polymers. Hence, the gels remain in wounds as in the case of hydrocolloid dressings, possibly inducing chronic inflammation. The two monomers thereof as the raw materials have higher toxicity, with possible development of toxicity due to the remaining monomers and decomposed products thereof.
Also, occlusive dressings such as polyurethane film and hydrocolloid are excellent in terms of the effect of facilitating healing. Once the dressings are infected with bacteria, however, the bacteria rapidly proliferate because the wet environment is a suitable medium for the bacteria, with a risk of triggering severe infection. For the infection, antibiotics are administered systemically or locally, but blood circulation is so poor at wounds with bacterial infection that an effective dose of antibiotics cannot be delivered to the wounds by the systemic administration, or side effects may occur by local administration due to the cytotoxicity of locally administered antibiotics.
Cyanoacrylate polymerizable adhesives to be used for biological tissues have problems in that the monomer is highly cytotoxic; fibrin glue has also problems in that the stable supply and the retention of the properties thereof are difficult because the glue is derived from living bodies and the glue may possibly be infected with virus.
Oxycellulose mesh to be used as an adhesion preventing agent is poor in handling because the mesh is in the form of fabric. Additionally, the mesh has poor biocompatibility. Therefore, such mesh is disadvantageous in that chronic inflammation might be induced.
Succinate or glutarate crosslinked amylose, dextran or pullulan, which can be produced by a production method disclosed in the Specification of U.S. Pat. No. 4,002,173, is preferable as a hemostatic agent. However, because such amylose, dextran or pullulan is in the form of solid matters, it lacks flexibility. As described in the Specification, it is essential that the solid matters should be modified into ground powder or sponge. Thus, the aforementioned amylose, dextran or pullulan cannot satisfy the transparency and occlusive potential demanded for wound dressings and adhesion preventing materials. Furthermore, the ester bond used for such crosslinking is readily hydrolyzed in an aqueous solution or in body fluid, and therefore, the properties as a water swelling gel are deteriorated over time. Additionally, solubilized matters increase, which is a problem from safety concern. In practical sense, these are for the purpose of the practical application as a hemostatic agent for a short term of several hours. Therefore, these can never endure the continuous use for several days to several months.
It is known crosslinked chitosan produced by reacting chitosan with an N-hydroxysuccinimide ester compound (see Japanese Patent Laid-open No. Hei 2-180903), and it is expected that the chitosan may be useful in the medical fields such as artificial skin. According to the Example, the crosslinked chitosan is rigid and therefore fragile with a breaking extension ratio of 30% or less, so that the chitosan cannot satisfy the elasticity and flexibility demanded for wound dressings and adhesion preventing materials. The chitosan is hydrolyzed in aqueous solution or body fluid because of the ester bonds present therein, generating solubilized matters and deteriorating the properties of the water swelling polymer gel.
It is known also a method of preventing tissue adhesion using a viscous and elastic fluid produced by ionically crosslinking temporarily a chitin derivative with sulfuric acid or aspartic acid or glutamic acid (see the Specification of U.S. Pat. No. 5,093,319), but because the crosslinking is via a reverse ion bonding, the properties of the resulting water swelling polymer gel are deteriorated in contact with a solution containing a higher concentration of salts, such as body fluid.
As has been described above, no water swelling polymer gel with all of the properties required for various medical use and concurrently with biocompatibility is found among conventionally known such gels in the current state.
Alternatively, polymer gels have been used in various applications in medical fields as described above. It has been proposed recently a drug delivery system (DDS) containing a pharmaceutical agent in a polymer gel or a wound dressing containing a pharmaceutical agent.
The examples are a crosslinked hyaluronate gel containing lipid microspheres with pharmaceutical agents encapsulated therein and being cleavable with OH radicals (see Yui, et al., Polymer Preprints, Japan, 42(8), pp. 3186-3188 (1993)); and cellulose powder bound, through -Phe-, -Tyr-, -Ile-Tyr- and -Gly-Ile-Tyr-, with pholcodine (see F. Lapicque & E. Dellacherie, J. Controlled Release, 4, pp. 39-45 (1983)). As wound dressings with pharmaceutical agents contained therein, it is known a wound contact pad as a part of a wound treating device, comprising a mixture alginate of an insoluble alginate salt and a soluble alginate salt, and containing an antibiotics or a local anesthesia (see the Specification of U.S. Pat. No. 5,238,685). It is also described a wound dressing containing hydrogel, as the structural component, in which a peptide promoting healing of wounds is covalently bonded at least at the surface and also containing, a disinfectant (see WO 92/3172).
By the drug delivery system in which drug encapsulated-lipid microspheres is contained in a crosslinked hyaluronate gel to be decomposed via OH radicals, the hyaluronate gel is decomposed at a site where OH radicals are generated to release the drug encapsulated-lipid microspheres. Because the generation of higher levels of OH radicals is limited to a certain stage of inflammation or to a very limited area of inflammation, however, the number of subjective diseases to which the system is applicable is relatively limited. Additionally, applicable drugs are substantially limited because drugs with lower fat solubility cannot be encapsulated into lipid microspheres. Furthermore, the drugs encapsulated into lipid microspheres are gradually released from the lipid microspheres into an external aqueous phase so that the drugs may be released also at a site besides the focal site, involving possible side effects. By a drug delivery system in which pholcodine is bound through -Phe-, -Tyr-, -Ile-Tyr-, and -Gly-Ile-Tyr- to cellulose powder, the drug immobilized onto the cellulose powder is tentatively released in the presence of an enzyme, but the release of the drug is as less as 1/1000 to 1/20,000 fold that of the immobilized drug. Thus, such system is not practical.
In the wound dressings disclosed in U.S. Pat. No. 5,238,685, drugs such as antibacterial agents and local anesthesia may be contained in a gel pad, but the drugs are consistently released because the drugs are not immobilized onto the gel, thus possibly inducing side effects. In the wound dressing disclosed in WO 92/3172, the surface thereof is chemically bound with a peptide for promoting wound healing and the bonding cannot be cleaved. Thus, the effect of the peptide can be exerted only at a site in contact to the wound dressing. If a disinfectant is contained in the structural component hydrogel, the disinfectant is consistently released, with concerns of the occurrence of side effects.
As has been described above, no conventionally known medical polymer gel can release a therapeutically effective dose of a drug only at a subjective focal site. Hence, a safer therapeutic system is now desired.
Thus, a first objective of the present invention is to provide a medical polymer gel capable of releasing a therapeutically effective dose of a drug only at a focal site generating an enzyme.
Furthermore, a second objective of the present invention is to provide a water swelling polymer gel, being highly transparent and having excellent biocompatibility, thermal resistance and stability, and being useful as the structural component of a variety of medical materials such as wound dressings, adhesives for biological tissues, adhesion preventing agents and the like.